Increased Cancer Risk Associated With The-607C/A Polymorphism In Interleukin-18 Gene Promoter:an Updated Meta-analysis Including 12,502 Subjects

Objective: Increasing investigations have been performed on the association of-607C/A polymorphism in Interleukin-18（IL-18）gene promoter with cancer risk and have yielded conflicting results.To derive a more precise estimation of the association,we performed an updated meta-analysis of all eligible studies.Methods（1）According to the requisition of systematic evaluation,we formulate detailed standardization of the inclusion and exclusion criteria including type of research,genotype distribution information available,and cancers diagnosed by histopathology.（2）A comprehensive literature search was performed in PubMed,MEDLINE,EMBASE,and CNKI（China National Knowledge Infrastructure）databases until November 29 th,2014.The following search terms were used:（“Interleukin-18” or “IL-18” or “rs1946518”）and（“polymorphism” or “SNP” or “mutation” or “genetic polymorphism” or “variation” or “single nucleotide polymorphism” or “variant”）and（“carcinoma” or “cancer” or “tumor” or “neoplasm”）.We also performed manual searches of references cited in the retrieved articles and previous reviews on the topic.（3）The strength of the association between the-607C/A polymorphism of IL-18 gene and cancer risk was measured by ORs and the corresponding 95% CI in the allelic model（A vs C）,homozygous model（AA vs CC）,heterozygous model（CA vs CC）,recessive model（AA vs CC/CA）and the dominant model（AA/CA vs CC）.The significance of pooled ORs was valued by the Z test and was considered statistically significant when p<0.05.Pearson’s x² test was performed to examine HWE,and p>0.05 was considered to be in line with HWE.Chi-square-based Q statistic test was performed in order to evaluate possible between-study heterogeneity（heterogeneity was considered statistically significant if p<0.10）.If there was no heterogeneity,the fixed-effect model was used according to the Mantel-Haenszel method;otherwise,the random-effects model（DerSimonian-Laird method）was applied.Both subgroup analyses and meta-regression analyses were performed to explore the source of heterogeneity among variables such as ethnicity,cancer type,source of controls and sample size.To evaluate the stability of the results,sensitivity analysis was conducted by deleting one single study each time.Moreover,Begg funnel plots and Egger’s regression test were undertaken to assess the potential publication bias,and a p<0.05 was considered significant.It is worth mentioning that if a specific cancer type was evaluated in fewer than two case-control studies,it would fall into the “other types” group.All of the statistical analyses were conducted by STATA（version 12.0;Stata Corporation,College Station,Texas,USA）.Results:（1）Characteristics of eligible studiesBased on our search strategy,28 eligible articles were identified.Two separate case-control studies were included from the study conducted by Haghshenas et al.and were considered separately.Thus,in all,we included 29 studies in this meta-analysis,with 6,026 cancer patients and 6,476 controls.（2）Meta-analysis resultsOverall,significant associations were detected between the-607C/A polymorphism in IL-18 gene promoter and cancer susceptibility(allelic model,A vs C,OR=1.10,95% CI: 1.01-1.19,P_{heterogeneity}=0.001;homozygous model,AA vs CC: OR=1.17,95% CI: 1.01-1.37,P_{heterogeneity}=0.007;heterozygous model,CA vs CC: OR=1.15,95% CI: 1.05-1.25,P_{heterogeneity}=0.152;dominant model,AA/CA vs CC: OR=1.17,95% CI: 1.06-1.31,P_{heterogeneity}=0.042).No significant association was found in the recessive model(recessive model,AA vs CC/CA: OR=1.06,95% CI: 0.93-1.20,P_{heterogeneity}=0.008).In the subgroup analysis by cancer type we found a significantly increased susceptibility to breast cancer(A vs C: OR =1.33,95% CI: 1.00-1.75,P_{heterogeneity}=0.155;AA vs CC: OR =1.80,95% CI: 1.02-3.21,P_{heterogeneity}=0.162;AA/CA vs CC: OR =1.33,95% CI: 1.00-1.78,P_{heterogeneity}=0.546),esophageal cancer(CA vs CC: OR=1.37,95% CI: 1.04-1.80,P_{heterogeneity}=0.528;AA/CA vs CC: OR =1.29,95% CI: 1.00-1.66,P_{heterogeneity}=0.700),and nasopharyngeal carcinoma(A vs C: OR =1.16,95% CI: 1.01-1.32,P_{heterogeneity}=0.921;AA vs CC: OR =1.34,95% CI: 1.02-1.75,P_{heterogeneity}=0.863;CA vs.CC: OR=1.36,95% CI: 1.08-1.70,P_{heterogeneity}=0.824;AA/CA vs CC: OR =1.35,95% CI: 1.09-1.68,P_{heterogeneity}=0.904).In subgroup analyses based on ethnicity,the results suggested a significantly increased risk of cancer in Asian population(CA vs CC: OR =1.11,95% CI: 1.00-1.24,P_{heterogeneity}=0.353;AA/CA vs CC: OR =1.14,95% CI: 1.02-1.29,P_{heterogeneity}=0.081)and in Mixed population(A vs C: OR=1.72,95% CI: 1.22-2.43,P_{heterogeneity}=NA;AA vs CC: OR=2.84,95% CI: 1.43-5.64,P_{heterogeneity}=NA;AA vs CC/CA: OR =2.43,95% CI: 1.34-4.42,P_{heterogeneity}=NA;AA/CA vs CC: OR =1.69,95% CI: 1.00-2.85,P_{heterogeneity}=NA);however,no significant association was found in Caucasian or African populations.Conclusions:（1）The current meta-analysis suggests that the-607C/A polymorphism in IL-18 gene promoter is associated with a significantly increased risk of cancer.（2）In respect of cancer type,the-607C/A polymorphism in IL-18 gene promoter is statistically related with an increased risk of breast cancer,esophageal cancer,and nasopharyngeal carcinoma.（3）In terms of ethnicity,the-607C/A polymorphism in IL-18 gene promoter is statistically related with an increased risk of cancer in Asian and Mixed populations.（4）Considering the limitations of our study,more studies with diverse ethnic groups,more cancer type,larger sample size,and well controlled confounding factors are warranted to further investigate the association.